Treatment of Candida infection in neonates

INTRODUCTION — Candida is an important cause of neonatal infections and is associated with significant morbidity and mortality, especially in extremely low and very low birth weight infants (defined as birth weights <1000 g and <1500 g, respectively). Successful management of neonatal candidiasis includes appropriate antifungal therapy and supportive care, as well as preventive measures to reduce the risk of systemic candidal infections.

The treatment of Candida infections in neonates will be reviewed here. The clinical manifestations, diagnosis, etiology, risk factors, and prevention of neonatal candidal infections are discussed separately. (See "Clinical manifestations and diagnosis of Candida infection in neonates" and "Epidemiology and risk factors for Candida infection in neonates" and "Prevention of Candida infection in neonates".)

In addition, the treatment of breastfeeding mothers with candidal skin infections is also presented elsewhere. (See "Common problems of breastfeeding and weaning", section on 'Candidal infection'.)

MANAGEMENT APPROACH — The treatment of candidal infections in neonates is based on the type and severity of infection, as discussed in the following sections. There are two broad categories of candidal infections in neonates:

●Noninvasive mucocutaneous candidiasis (eg, thrush, diaper dermatitis) (see 'Mucocutaneous candidiasis' below)

●Invasive infections (which can involve the bloodstream, urinary tract, central nervous system [CNS], and other focal sites) (see 'Invasive infection' below)

Our management approach is generally consistent with the recommendations of the Infectious Diseases Society of America and the American Academy of Pediatrics [1,2].

Mucocutaneous candidiasis

Low risk of systemic infection — Neonates with noninvasive mucocutaneous candidiasis (ie, thrush, diaper dermatitis) are generally at low risk of disseminated systemic infection and can be treated with topical antifungal therapy.

Risk factors for invasive candidiasis are discussed in greater detail separately. (See "Epidemiology and risk factors for Candida infection in neonates", section on 'Risk factors for invasive candidiasis'.)

Appropriate topical antifungal agents for noninvasive mucocutaneous candidiasis include nystatin and azole topical preparations. Systemic antifungal agents are used only if the infection is refractory to topical therapy. When systemic therapy is deemed necessary, fluconazole (3 mg/kg once a day for seven days) is our preferred agent in most cases because it is well tolerated and effective in neonates [3]. (See 'Fluconazole' below and "Oropharyngeal candidiasis in adults", section on 'Treatment'.)

Oral candidiasis — Nystatin, a polyene topical antifungal agent, is our preferred initial agent to treat oral candidiasis (thrush) as it is not absorbed systemically from the gastrointestinal tract. It is administered as an oral suspension (100,000 units/mL) at a dose of 0.5 mL to each side of the mouth four times a day between feeds for 5 to 10 days. Reported cure rates with oral nystatin suspension range from 29 to 85 percent [3,4]. Oral miconazole gel (not available in the United States) has a better cure rate (>90 percent), but systemic absorption may occur and gastrointestinal side effects are reported in 6 percent of premature neonates [4]. Neonates with inadequate response to topical nystatin can be treated with oral fluconazole (3 mg/kg once a day for seven days).

In healthy term infants who lack symptoms, are feeding well, and are at low risk of invasive candidiasis, oral candidiasis may not require treatment. Data concerning treatment in this setting are lacking. The National Institute for Health and Care Excellence guidelines suggest that thrush should be treated with an appropriate antifungal medication if the symptoms are causing pain to the mother or the baby or feeding concerns to either [5]. Other experts prefer to treat all infants, including low-risk and asymptomatic neonates.

Measures to prevent reinfection include sterilization or decolonization of items that are placed in the infant's mouth (eg, bottle nipples and pacifiers).

Diaper dermatitis — Diaper dermatitis is treated with topical nystatin or azole cream (eg, miconazole or clotrimazole cream) [4]. Nystatin usually is effective and is generally the least expensive option. (See "Diaper dermatitis".)

High risk of systemic infection — In patients with mucocutaneous candidiasis with a high likelihood of systemic infection (eg, congenital cutaneous candidiasis [CCC], invasive dermatitis), we suggest initiating systemic antifungal therapy while awaiting the results of blood and other cultures. A full evaluation should be performed to determine the extent of dissemination, which informs the duration of therapy. (See 'Evaluation for extent of dissemination' below.)

Congenital cutaneous candidiasis — Based on limited data, we suggest systemic antifungal therapy for neonates with CCC [6,7]. For premature infants and infants with complicated infection (clinical signs of sepsis or respiratory distress), amphotericin B is appropriate therapy [6]. Term infants who are tolerating feeds can be treated with oral fluconazole. (See 'Amphotericin B' below and 'Fluconazole' below.)

Neonates with CCC are at risk for dissemination to the bloodstream, urine, or cerebrospinal fluid (CSF). CCC occurs most commonly in low birth weight, preterm infants, but it can also affect term infants. The risk of dissemination is greatest in extremely low birth weight (ELBW; birth weight <1000 g) infants [6,7]. In a retrospective case series of 21 infants with CCC (18 preterm and 3 term; mean birth weight 950 g), all but one infant were treated with systemic antifungal therapy within 48 hours of rash presentation. Disseminated infection occurred in two infants (one was the infant in whom systemic antifungal therapy was delayed; the other presented shortly after birth with disseminated infection) [7]. There was only one death in this series (the infant with early disseminated disease). These data provide limited evidence that prompt systemic therapy may reduce the risk of systemic infection and mortality. Earlier reports indicated that systemic infection developed in up to two-thirds of ELBW neonates with CCC, with mortality rates of up to 40 percent [6].

Invasive fungal dermatitis — Invasive fungal dermatitis is a condition that is unique to ELBW infants (birth weight <1000 g) during the first two weeks after birth. Most affected patients have evidence of disseminated fungal disease. Thus, we suggest initiating systemic therapy with amphotericin B while awaiting culture results. (See 'Amphotericin B' below and "Clinical manifestations and diagnosis of Candida infection in neonates", section on 'Invasive fungal dermatitis'.)

Invasive infection — Management of neonates with invasive Candida infection, including bloodstream, urinary tract, CNS, and/or other invasive focal infection, involves the following components [1,2,8]:

●Evaluation to assess the extent of dissemination. (See 'Evaluation for extent of dissemination' below.)

●Removal of any source of infection (eg, central venous catheter [CVC], urinary catheter). (See 'Catheter-associated candidemia' below and 'Urinary tract infection' below and 'Persistent infection' below.)

●Administration of systemic antifungal agents. Amphotericin B is the preferred drug for the treatment of most systemic neonatal candidal infections. (See 'Systemic antifungal agents' below.)

Evaluation for extent of dissemination — Infants who are diagnosed with Candida infection involving the bloodstream, urinary tract, CNS, eyes, heart valves, bone, or joints should undergo evaluation for systemic disseminated infection, which informs management decisions. The following tests should be performed:

●Cultures of the blood, urine, and CSF

●Dilated eye examination to evaluate for endophthalmitis (picture 1)

●Echocardiography to assess for cardiac thrombi or vegetations

●Ultrasonography of the liver, spleen, kidneys, and bladder

●Head ultrasound

The diagnostic approach is discussed in greater detail separately. (See "Clinical manifestations and diagnosis of Candida infection in neonates", section on 'Evaluation for extent of dissemination'.)

Catheter-associated candidemia — For catheter-associated candidemia without evidence of dissemination, we suggest treatment with amphotericin B (1 mg/kg per dose given intravenously [IV] once daily) and removal of the CVC. The duration of therapy is typically 14 days from the first negative culture. (See 'Amphotericin B' below.)

Fluconazole (12 mg/kg given IV once daily) is an acceptable alternative for susceptible isolates. (See 'Fluconazole' below and 'Therapy based on susceptibility' below.)

In addition to systemic antifungal therapy, the CVC should be removed as soon as possible. The CVC serves as a focus for Candida, and removing it helps to clear the infection. In a retrospective study of 104 neonates with CVC-associated candidemia cared for in the neonatal intensive care unit setting, early removal of the CVC (within three days of the first positive blood culture) was associated with shorter duration of candidemia (median of three versus six days) and lower mortality (0 versus 39 percent) compared with late CVC removal (>3 days after first positive culture) [9].

Urinary tract infection — For treatment of Candida urinary tract infections (UTIs), we suggest amphotericin B (1 mg/kg per dose IV once daily) for 10 to 14 days. In addition, the urinary catheter, if present, should be removed. As with CVCs, the urinary catheter serves as a focus for Candida and removing it helps to clear the infection. (See 'Amphotericin B' below.)

Fluconazole (12 mg/kg given orally or IV once daily) is an acceptable alternative for susceptible isolates. Isolated uncomplicated UTI can be treated with oral fluconazole if the infant is clinically stable and tolerating feeds. IV fluconazole is preferred for complicated UTIs (eg, associated with fungal mass). (See 'Fluconazole' below and 'Therapy based on susceptibility' below.)

As previously discussed, ultrasonography of the bladder and kidneys should be performed to determine if there is renal parenchymal infiltration, calyceal mycetoma, or fungal masses in the urinary tract (see 'Evaluation for extent of dissemination' above). If a renal fungal mass is seen on ultrasonography, we typically continue treatment until there is complete resolution of the fungal abscess or mass by imaging. Though some studies suggest that ultrasonography correlates poorly with the course of the infection and patient outcome [10,11], we continue to use ultrasonography to guide duration of therapy because alternative diagnostic/prognostic tools are not available. The clinical status of the patient is also an important consideration in determining the duration of treatment.

Central nervous system infection — For most neonates with Candida CNS infection, we suggest amphotericin B monotherapy (1 mg/kg per dose IV once daily) [2]. Therapy continues for at least three weeks and should be continued until clinical signs, CSF abnormalities, and radiographic abnormalities (if present) have resolved. (See 'Amphotericin B' below.)

CNS devices (eg, shunts and ventriculostomy drains), if present, should be removed if possible [1].

If the CSF does not become sterile within a few days or if the patient's clinical status deteriorates despite treatment with amphotericin B monotherapy, flucytosine (25 mg/kg per dose given orally every six hours) can be added to the regimen [1,2]. (See 'Flucytosine' below.)

Disseminated disease — For neonates with disseminated disease, we suggest amphotericin B (1 mg/kg per dose IV once daily). (See 'Amphotericin B' below.)

Monotherapy with fluconazole (12 mg/kg given IV once daily) is an acceptable alternative for susceptible isolates if CNS infection has been excluded and the course is otherwise uncomplicated. (See 'Fluconazole' below and 'Therapy based on susceptibility' below.)

The optimal duration of therapy is unclear. Our approach is as follows:

●Uncomplicated candidemia without focal infection – Based upon the limited available data, we treat neonates with uncomplicated candidemia (ie, without a focal infection) for a minimum of 14 days after the first sterile blood culture and resolution of signs attributable to candidemia [1].

●CNS infection – Treatment for Candida CNS infection should be administered for at least three weeks and until all clinical signs, CSF abnormalities, and CNS imaging abnormalities have resolved. (See 'Central nervous system infection' above.)

●Complicated candidemia associated with focal infection – Candidemia associated with focal infections (eg, endocarditis, renal fungal masses) is often persistent and/or difficult to eradicate. Prolonged therapy is generally warranted in these infants (usually four to six weeks). Surgical removal of the foci may also be necessary in some cases [1]. The duration of therapy is individualized based upon sterilization of blood cultures, resolution of clinical signs, and resolution of imaging findings.

Persistent infection — In instances where clearance of candidemia is not observed after primary treatment with amphotericin B, a second agent (eg, fluconazole or an echinocandin) is added. There is a paucity of evidence to guide the best combination therapy in such neonatal cases [12]. (See 'Fluconazole' below and 'Echinocandins' below.)

All potentially contaminated indwelling foreign material should be removed (eg, CVCs, urinary catheters, ventriculostomy drains). Surgical resection of infected tissue may be needed if systemic antifungal therapy is not successful in eradicating the infection or if the infected tissue causes functional impairment. Functional impairment may be seen in patients with a fungal mass causing urinary obstruction or hemodynamic compromise of the right atrium [13-16].

Therapy based on susceptibility — In all patients with positive cultures, the Candida species and its susceptibility to antifungal agents should be determined. Based upon the results, the choice of antifungal agent can be modified, if appropriate. If the species is susceptible to amphotericin B, monotherapy is the preferred choice of therapy. Fluconazole is an alternative agent for susceptible isolates.

Although amphotericin B is effective for treating most neonatal invasive Candida infections, there are reports of systemic infections with Candida species that are refractory (eg, Candida glabrata and Candida krusei) or resistant (eg, Candida lusitaniae) to amphotericin B. (See "Management of candidemia and invasive candidiasis in adults".)

SYSTEMIC ANTIFUNGAL AGENTS — The four different classes of antifungal agents used to treat invasive neonatal candidiasis are [17]:

●Polyenes – Polyenes include amphotericin B deoxycholate, which is the preferred antifungal agent for most invasive neonatal Candida infections [1,2].

●Triazoles – The most commonly used triazole in neonates is fluconazole.

●Nucleoside analogues – The most commonly used nucleoside analogue in neonates is flucytosine. It is sometimes used in combination with amphotericin B in neonates with central nervous system (CNS) infections.

●Echinocandins – Echinocandins include caspofungin, anidulafungin, and micafungin. These drugs are not routinely used for neonatal Candida infections.

Amphotericin B — Amphotericin B deoxycholate is the preferred drug for treatment of most systemic neonatal Candida infections [2]. Most Candida species are susceptible to amphotericin B, and this drug is efficacious and well tolerated in neonates [2,18-20].

Dose — Amphotericin B is administered intravenously (IV) at a dose of 1 mg/kg every 24 hours [2,19]. After completing one week of therapy with daily dosing, therapeutic serum concentrations can be maintained by administering 1.5 mg/kg per dose IV every other day; however, this practice is not routine [2].

The dose of amphotericin B generally does not need be adjusted in patients with preexisting renal insufficiency. However, if there is renal toxicity thought to be drug related, the dose should be reduced (either by using alternate-day dosing or reducing the daily dose by 50 percent).

An initial test dose (sometimes given to children and adults receiving amphotericin B) is not necessary in infants, because of the lower rate of infusion-related side effects. (See 'Side effects' below.)

Side effects — Adverse effects of amphotericin appear to be less common and less severe in neonates than in older children and adults. Although there is a potential for nephrotoxicity and hypokalemia due to renal losses, it appears that most infants display no or only transient nephrotoxicity [21]. This was illustrated in a retrospective review of 92 infants <90 days of age (median gestational age 26 weeks) who received at least three doses of amphotericin [22]. Nephrotoxicity (defined as an increase in serum creatinine of 0.4 mg/dL) developed in 16 percent of patients, though maximum creatinine values did not exceed 2 mg/dL. In addition, 17 percent developed hypokalemia (defined as serum potassium <3 mEq/L), which was more likely in patients with nephrotoxicity. By the end of amphotericin therapy, creatinine levels returned to baseline in eight patients, were decreasing in three patients, and remained elevated in four patients. Amphotericin therapy was not discontinued, and there was no dose reduction in any of the patients. There was no difference between infants who did or did not develop nephrotoxicity in terms of gestational age, birth weight, sex, underlying medical conditions, use of other potentially nephrotoxic medications or amphotericin exposure, and duration of therapy.

Other reported adverse effects include hypomagnesemia caused by excessive renal losses, bone marrow suppression with anemia and thrombocytopenia, and an increase in hepatic enzymes. These abnormalities are infrequent, dose dependent, and resolve with cessation of the drug.

Monitoring — Because of the potential adverse effects, infants receiving amphotericin B should have regular laboratory monitoring. In our practice, we monitor the following laboratory studies:

●Serum electrolytes (including potassium and magnesium) daily or every other day

●Serum creatinine daily or every other day initially and, if stable, testing can be spaced to twice weekly

●Complete blood count with differential and platelet count twice a week initially and, if stable, testing can be spaced to once a week

●Liver enzymes (alanine aminotransferase and aspartate aminotransferase) twice a week initially and, if stable, testing can be spaced to once a week

Amphotericin B lipid formulations — We suggest conventional amphotericin B (ie, amphotericin B deoxycholate) over the lipid-based amphotericin B formulations. The lipid formulations do not appear to be superior to the less expensive amphotericin B deoxycholate. They are typically reserved for patients who develop intolerant infusion-related reactions or renal dysfunction during standard amphotericin B administration. The lipid formulations should not be used in patients with Candida urinary tract infections (UTIs).

Lipid-based amphotericin B formulations have the ability to deliver a higher dose of medication with lower levels of toxicity but are significantly more expensive than standard amphotericin B. Data on the use of these agents in neonates are limited to case reports and case series [23-27]. Most reports show that lipid-based amphotericin B preparations successfully treated neonates with candidemia and were not associated with any major adverse effects. However, in a multicenter retrospective review of 730 infants with positive blood, urine, or cerebrospinal fluid (CSF) cultures for Candida species, multivariate analysis showed higher mortality for infants receiving amphotericin B lipid products compared with infants receiving amphotericin B deoxycholate (odds ratio 1.96, 95% CI 1.16-3.33) or fluconazole (odds ratio 2.39, 95% CI 1.18-4.83) [28].

Fluconazole — Fluconazole, a first-generation triazole, is an alternative to amphotericin B in some infants, if the isolate is susceptible. Fluconazole has several advantages:

●Excellent therapeutic levels throughout the body including the CSF [29]

●Excellent agent for the treatment of Candida UTI because it is excreted unchanged in high concentrations into the urine

●Excellent bioavailability when taken orally, potentially reducing the need for IV administration

The major disadvantage of this agent is the emergence of fluconazole-resistant Candida species, such as C. krusei, C. glabrata, and Candida parapsilosis. The use of fluconazole prophylaxis to reduce Candida infections may also be a contributing factor to fluconazole resistance. (See "Prevention of Candida infection in neonates" and "Management of candidemia and invasive candidiasis in adults".)

Thus, fluconazole should not be used as the agent for initial treatment of an infant with candidemia or suspected candidemia. It should be given only after identifying the Candida species and determining that the organism is sensitive to fluconazole. This is especially important if prior fluconazole prophylaxis has been given to the infant.

For treatment of systemic candidiasis, fluconazole dosing for susceptible isolates consists of a an initial loading dose of 25 mg/kg IV followed by 12 mg/kg per dose IV once daily [2,30]. IV administration is generally preferred over oral for the treatment of invasive infections. Oral fluconazole may be appropriate for treatment of isolated uncomplicated UTI and for mucocutaneous candidiasis, including congenital cutaneous candidiasis (CCC) in term infants who are clinically stable and tolerating full enteral feeding.

The dosing interval may be extended to 48 hours in extremely premature infants with impaired renal clearance. One small study involving only eight infants demonstrated that administering an initial loading dose achieved therapeutic levels more rapidly than the standard regimen without a loading dose [31]. However, larger studies are needed to confirm that this is a safe and more effective dosing regimen before it can be recommended as standard practice. Centers should consider the minimum inhibitory concentration range of the isolates of colonizing Candida species found in their unit when deciding on the dosing regimen.

Lower doses (3 to 6 mg/kg twice weekly) are typically used for antifungal prophylaxis in preterm infants when such prophylaxis is warranted. Antifungal prophylaxis is discussed separately. (See "Prevention of Candida infection in neonates", section on 'Antifungal prophylaxis'.)

The efficacy of fluconazole for treatment of invasive candidiasis is supported by two small prospective studies [32,33]. In a randomized trial in 23 infants with proven fungal septicemia randomly assigned fluconazole (IV or enterally) or amphotericin B, infants in the fluconazole group required fewer days of IV therapy [33]. However, mortality rates were high in both groups (3 of 12 patients in the fluconazole group versus 5 of 11 patients in the amphotericin B group). Patients who received fluconazole appeared to have less hepatotoxicity with lower serum bilirubin and alkaline phosphatase concentrations [30,31].

Second-generation triazoles, such as voriconazole, have been developed with a broader spectrum of activity and increased potency. In adult trials, they are effective in fluconazole-resistant species, but there are no comparable data in neonates. (See "Management of candidemia and invasive candidiasis in adults".)

Flucytosine — In neonates, use of flucytosine is mostly limited to treatment of CNS infections that do not respond to monotherapy with amphotericin B. In this setting, flucytosine is used in combination with amphotericin B because it has excellent penetration into the CSF and is synergistic with amphotericin B [18].

Drawbacks of this agent in neonates include its considerable side effect profile, rapid development of resistance when used as monotherapy, and lack of availability of a parenteral formulation, thus limiting its use in critically ill neonates. (See "Pharmacology of flucytosine (5-FC)", section on 'Adverse effects'.)

The oral dose is 50 to 150 mg/kg per day divided into four doses at six-hour intervals. It is critical to monitor blood levels of flucytosine to avoid bone marrow toxicity. Peak plasma concentrations obtained 60 to 120 minutes after administration should be maintained between 40 and 60 mcg/mL, and trough levels obtained prior to the next dose should be less than 25 mcg/mL. Bone marrow suppression is increased with sustained levels greater than 100 mcg/mL.

Echinocandins — Echinocandins, which include caspofungin, anidulafungin, and micafungin, are not routinely used in neonates. They may be considered in infants for whom the use of fluconazole and amphotericin is precluded because of drug toxicity or antifungal resistance [34]. These agents appear to be well tolerated with a minimum of adverse effects in adult patients, but data in neonates are limited. Resistance to this class of antifungal agents is uncommon. Echinocandins appear to be a promising class of antifungal agents in the treatment of neonatal candidemia. Some experts have proposed using micafungin as a first-line antifungal agent in preterm neonates [8]; however, further data on their efficacy, safety, and dosing regimen in neonates are needed before echinocandins can be recommended for routine use.

●Micafungin – The efficacy and safety of micafungin in neonates are supported by observational data and small clinical trials [35-42]. In a systematic review of nine clinical trials evaluating the safety and efficacy of micafungin in infants <2 years (116 patients, 48 percent preterm infants), micafungin had good efficacy (73 percent treatment success among patients with invasive candidiasis) and was well tolerated without serious side effects [39]. In a subsequent clinical trial in 30 infants (most were ≤4 weeks old) with invasive candidiasis randomized to treatment with micafungin or amphotericin B, the rate of complete or partial clinical response after one week was similar in both groups (61 and 70 percent, respectively). The rate of treatment-associated adverse events was also similar in both groups (55 and 50 percent, respectively), with transient anemia and thrombocytopenia being the most common.

●Caspofungin – A small multicenter randomized trial compared caspofungin with amphotericin B in 47 neonates and young infants with invasive candida infection [43]. At two weeks, the proportion of infants who were alive and free of infection was similar in both groups (71 versus 69 percent); adverse events occurred less commonly in the caspofungin group (85 versus 100 percent). However, the trial was stopped early due to low enrollment and, as such, it may have been inadequately powered to detect important differences in outcomes.

OUTCOME — The prognosis of preterm infants with invasive candidal infections is guarded, with reported mortality rates of approximately 20 to 40 percent among extremely low birth weight infants (ELBW; birth weight <1000 g) [44-51]. Survivors of neonatal candidemia, especially in those with central nervous system (CNS) involvement, are at risk of long-term neurodevelopmental impairment [44-47,52].

PREVENTION — Preventive measures to reduce the risk of developing candidal infections include efforts to reduce Candida cross-transmission and risk factors associated with fungal infections, as well as the use of prophylactic antifungal agents. These issues are discussed in a separate topic review. (See "Prevention of Candida infection in neonates".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Candidiasis".)

SUMMARY AND RECOMMENDATIONS

●Noninvasive mucocutaneous candidiasis – For most neonates with noninvasive mucocutaneous candidiasis (ie, thrush, diaper dermatitis), we suggest topical antifungal therapy rather than systemic therapy (Grade 2B). The choice of therapy is as follows (see 'Mucocutaneous candidiasis' above):

•For neonates with oral candidiasis (thrush), we suggest treatment with oral nystatin rather than other topical agents (Grade 2C). Nystatin is administered as an oral suspension (100,000 units/mL) at a dose of 0.5 mL to each side of the mouth four times a day between feeds for 5 to 10 days. Oral miconazole gel is an alternative option, but it has a high rate of side effects in preterm infants. No specific treatment is a reasonable alternative in healthy term infants who lack symptoms, are feeding well, and are at low risk of invasive candidiasis. (See 'Oral candidiasis' above.)

•For neonates with diaper dermatitis, we suggest treatment with topical nystatin or azole cream (eg, miconazole or clotrimazole cream) (Grade 2C). Nystatin usually is effective and is generally the least expensive option. (See 'Diaper dermatitis' above.)

•Systemic antifungal agents are used for mucocutaneous infections only if the infection is refractory to topical therapy or if there is high risk of systemic infection (eg, congenital candidiasis, invasive dermatitis). (See 'High risk of systemic infection' above.)

●Invasive Candida infections – Management of neonates with invasive Candida infections, including bloodstream, urinary tract, central nervous system (CNS), and/or other invasive focal infection, involves the following components:

•Evaluation to assess the extent of dissemination (see 'Evaluation for extent of dissemination' above)

•Removal of any source of infection (eg, central venous catheter [CVC], urinary catheter) (see 'Catheter-associated candidemia' above and 'Urinary tract infection' above and 'Persistent infection' above)

•Administration of systemic antifungal agents (see 'Systemic antifungal agents' above)

●Choice of systemic antifungal agent – For most neonates with invasive Candida infection, we suggest amphotericin B for initial therapy rather than other systemic antifungal agents (Grade 2C). The dose of amphotericin B is 1 mg/kg given intravenously (IV) once daily. Once results of susceptibility testing are available, therapy should be modified if the organism is resistant to amphotericin B. IV fluconazole is a reasonable alternative to amphotericin B if the isolate is susceptible. (See 'Invasive infection' above and 'Amphotericin B' above and 'Therapy based on susceptibility' above.)

●Duration of therapy – The duration of therapy depends on the type of infection, as follows:

•Uncomplicated candidemia (including CVC-associated candidemia) – For neonates with candidemia and no evidence of metastatic foci of infection, treatment is continued for a minimum of 14 days after the first sterile blood culture and resolution of signs attributable to candidemia. If a CVC is present, it should be removed as soon as possible. (See 'Catheter-associated candidemia' above and 'Disseminated disease' above.)

•Uncomplicated urinary tract infection (UTI) – For neonates with candidal UTI and no evidence of fungal abscess or mass on imaging, treatment is continued for 10 to 14 days. The urinary catheter, if present, should be removed as soon as possible. (See 'Urinary tract infection' above.)

•CNS infection – Treatment continues for a minimum of three weeks and should be continued until all clinical signs, cerebrospinal fluid (CSF) abnormalities, and radiographic abnormalities (if present) have resolved. CNS devices (eg, shunts and ventriculostomy drains), if present, should be removed whenever possible. If the CSF does not become sterile within a few days or if the patient's clinical status deteriorates despite treatment with amphotericin B monotherapy, flucytosine (25 mg/kg per dose given orally every six hours) can be added to the regimen. (See 'Central nervous system infection' above.)

•Disseminated disease with focal infection sites – Candidemia associated with metastatic foci of infection (eg, endocarditis, renal fungal masses) is often persistent and/or difficult to eradicate. The duration of therapy is individualized based upon sterilization of blood cultures, resolution of clinical signs, and resolution imaging findings. Prolonged therapy is generally warranted. Surgical removal of the infected foci may also be necessary in some cases. (See 'Disseminated disease' above.)

●Monitoring during therapy – Infants receiving amphotericin B should have serial monitoring with the following laboratory studies (see 'Monitoring' above):

•Serum electrolytes (including potassium and magnesium) daily or every other day

•Serum creatinine daily or every other day initially and, if stable, testing can be spaced to twice weekly

•Complete blood count with differential and platelet count twice a week initially and, if stable, testing can be spaced to once a week

•Liver enzymes (alanine aminotransferase and aspartate aminotransferase) twice a week initially and, if stable, testing can be spaced to once a week

●Prognosis – The prognosis of invasive candidal infections in preterm infants is guarded, with reported mortality rates of approximately 40 in extremely low birth weight (ELBW) infants. (See 'Outcome' above.)